1. Field of the Invention
This invention relates to a novel process for the preparation of antihypertensive agents, comprising fermentation of compound (V) ##STR2## with the microorganism Streptomyces sp. MA6744, to obtain four biotransformation products, compounds (I), (II), (III) and (IV), represented by the structural formula ##STR3## where in compound (I), R.sup.1 =--CH.sub.2 OH, R.sup.2 =--H and R.sup.3 =--H (7-hydroxymethyl analog); in compound (II), R.sup.1 =--CH.sub.2 OH, R.sup.2 =--OH and R.sup.3 =--H (5,7-dihydroxymethyl analog); in compound (III), R.sup.1 =--COOH, R.sup.2 =--H and R.sup.3 =--H (7-carboxy analog); and in compound (IV), R.sup.1 =--CH.sub.3, R.sup.2 =--OH and R.sup.3 =--OH (1'-hydroxy-5-hydroxymethyl analog). Compounds (I), (II), (III), (IV) and their precursor (V) are Angiotensin II (A II) receptor antagonists useful in the treatment of human hypertensive diseases.
A II is an octapeptide hormone produced mainly in the blood during the cleavage of Angiotensin I by angiotensin converting enzyme (ACE). ACE is localized on the endothelium of blood vessels of lung, kidney and many other organs. A II is the end product of the renin-angiotensin system (RAS), a system that plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance, as well as congestive heart failure. A II is a powerful arterial vasconstrictor that exerts its action by interacting with specific receptors present on cell membranes. A II receptor antagonism is one of the possible modes of controlling the RAS.
2. Brief Description of Disclosures in the Art
Copending U.S. application Ser. No. 516,286, filed May 4, 1990, discloses the substrate compound used in this invention and designated herein as compound (V), and also generically covers the 7-hydroxymethyl, 5,7-dihydroxymethyl, 7-carboxy and 1'-hydroxy-5-hydroxymethyl oxidation products of this invention.